Among many viral and non-viral genetic vector systems, Herpes Simplex Virus (HSV)-based vectors have been investigated for use as gene transfer vectors, including for possible therapeutic use in human patients. HSV is a complex, non-integrating DNA virus capable of infecting a very wide range of human and animal cells. The viral genome contains more than 80 genes and is composed of two unique segments, UL and US, each flanked by inverted repeats that encode critical diploid genes. An important feature of HSV replication is the expression of its genes in waves referred to as cascade regulation (Rajcani, Virus Genes, 28: 293-310 (2004)). Removal of the essential immediate-early (IE) genes ICP27 and ICP4 renders the virus completely defective and incapable of expression of early (E) genes involved in viral genome replication and late (L) genes functioning in progeny virion assembly. These replication-defective viruses can be grown on complementing cells that express (complement) the missing ICP4 and ICP27 gene products and can then be used to infect non-complementing cells where the viral genome takes residence as a stable nuclear episome. However, vectors that preserve the ICP0 and ICP22 IE genes are toxic to cells, but inactivation or deletion of these genes, the ICP0 gene in particular, hampers transgene expression.
Accordingly, there remains a need for an HSV vector capable of expressing a transgene in any tissue or cell, in vitro or in vivo, without harming the cell or tissue and a system for propagating such vectors.